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The Potential of Sugar Chains for Diagnosis and Treatment of Disease
Sugar, the "Face" of Cells
Protruding from the surface of all 60 trillion cells in the body, like whiskers on a face, are sugar chains, a biological structure often bound to proteins and lipids embedded in the cell membrane. Recent studies have shown that sugar chains exhibit a broad range of functions, including signal transduction between cells and across the cell membrane, as well as functional regulation of immunity and hormones. "From among the diverse functions of sugar chains, we focus on their association with disease," says Naoyuki Taniguchi, Group Director of the Systems Glycobiology Research Group at the RIKEN Advanced Science Institute and a world-renowned researcher in sugar chains. "The ultimate goal of our research is to clarify the mechanisms of the onset of disease in terms of sugar chains and to diagnose and treat disease using those mechanisms." Taniguchi's research is probing the frontiers of sugar chain science (glycobiology) for the diagnosis and treatment of disease.
"The sugar chain is like the face of the cell," says Taniguchi. "When we communicate with other people, we look at their face to identify them. Likewise, cells, as well as proteins and many other biological molecules, recognize sugar chains exposed to cell surfaces and bind to them to achieve mutual communication. Viruses, bacteria, and pathogenic toxins also recognize sugar chains, bind to them, and invade cells. When cells become cancerous, the sugar chains change and adopt a structure specific to cancer cells. Hence, the sugar chain comes to be the 'face' of the cancer cell."
Sugar Chains - A More Reliable Biomarker For Cancer Detection
Although sugar chains are involved in all biological phenomena, including development, differentiation and immunity, they have only been studied actively in the last 15 years or so. "The sugar chain is also called 'the third chain of life.' However, it is much more difficult to study than the first and second chains of life - DNA and proteins," says Taniguchi. "Most currently available biomarkers are glycoproteins or glycolipids. For example, an antibody that binds specifically to the protein moiety of a glycoprotein is created, and the protein is quantified. However, this does not provide an accurate diagnosis because there is no difference between the proteins of glycoproteins produced by normal cells and those produced by cancer cells," says Taniguchi. In fact, many people have elevated PSA levels but do not have prostate cancer, whereas others have normal PSA levels even though they have prostate cancer. More than 20 years ago, Taniguchi proposed for the first time in the world that sugar chains, rather than the proteins in glycoproteins, could be used as biomarkers. "The structures of sugar chains are known to change due to the attachment or removal of their sugars upon onset of disease," he explains.
In 1983, Taniguchi demonstrated that the y-GTP (gamma glutamyl transpeptidase) sugar chain in normal cells is bifurcated, and that the y-GTP sugar chain of cancer cells assumes a 'bisect' structure with one molecule of the N-acetylglucosamine sugar bound to the base of the branch. He later discovered the gene for the glcyosyltransferase GnT-III, which catalyzes the formation of the structure. "By utilizing structural changes in sugar chains, it is possible to examine the cancerization of cells earlier and more accurately. When cancer starts, up to several molecules of fucose sugar attach to the structure of alpha-fetoprotein, which is a biomarker for liver cancer, and haptoglobin, which is a biomarker for pancreatic cancer. A technology for detecting alpha-fetoprotein with one fucose attached to it is already available for practical use, and we are now working to develop biomarkers for a variety of cancers based on structural changes in sugar chains to detect various cancer cells."
New Sugar Chain Cancer Therapy Developing
Sugar chains are also closely related to cancer metastases. The glycosyltransferase GnT-V, which was discovered around the same time independently by Taniguchi and a US research group, attaches N-acetylglucosamine to the end of a sugar chain to bifurcate it. Cancer cells having a sugar chain with this structure are highly metastatic, whereas those having a sugar chain with a bisect structure produced by the glycosyltransferase GnT-III are non-metastatic. "It has been confirmed that cancer metastases decrease with the transfer of GnT-III to cancer cells. We are now working on this glycosyltransferase in the hope of developing new cancer therapeutics," said Dr. Taniguchi.
Sugar Chains and COPD In addition to cancer research, Dr. Taniguchi discovered sugar chains critical to the onset of chronic obstructive pulmonary disease (COPD). The swelling of alveoli - the tiny air sacs in the lungs - occurs due to excess activation of matrix metalloprotease (MMP), a protein-degrading enzyme, which causes the alveolar wall to collapse. In normal mice, the TGF-B molecule binds to its receptor in the cell membrane to generate a signal for suppressing the expression of MMP, thus preventing the collapse of the alveolar wall. "When we examined the sugar chain attached to the TGF-B receptor, we found that the core fucose structure was present in normal mice but absent in FUT 8 knockout mice. Because the Fut 8 knockout mice lack the core fucose structure, TGF-B cannot bind to the receptor in their body. As a result, the signal for suppressing the expression of MMP is not functioning, so the alveolar wall is destroyed by the activated MMP. This proved to be the mechanism of the onset of COPD." More Studies in the Broad Influences of Sugar As sugar chains are involved in all biological phenomena and diseases, the scope of research at the Diseases Glycomics Team is broad. In addition to the work described above, diverse studies are being conducted under the leadership of Shinobu Kitazume, depute head of the laboratory, including the development of an early diagnostic for Alzheimer's disease using sugar chains attached to a B-amyloid precursor protein, and the development of a new type of neovascularization inhibitor that targets sugar chains. Clearly the science of glycobiology continues to move in dramatic directions across the world. The findings and discoveries involving the diagnosis and treatment of disease will continue to grow exponentially. It is an exciting time to live! |
